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PubMed1990

Modulation of extracellular matrix components during dimethylnitrosamine-induced cirrhosis.

Liver fibrosis was induced in rats after administration of dimethylnitrosamine (DMN) intraperitoneally three times a week for 3 weeks. Incomplete septa appeared after 7 days and evidence of nodulation of the parenchyma was observed after 21 days. Both distribution of extracellular matrix components (collagen type I, type III and type IV, laminin, fibronectin, heparan sulphate proteoglycan) and the distribution of desmin as a marker of lipocytes (Ito cells) and of iso-alpha-smooth muscle actin were studied with immunoperoxidase. Changes in the distribution of extracellular matrix components outlined both the formation of septa and the development of nodules with changes in the sinusoidal pattern evoking aspects of capillarization. The number of desmin-positive cells increased in DMN-treated animals, showing a prominent reaction in the fibrous septa. In the normal liver, lipocytes were positive for laminin and negative for actin, but septal and juxta-septal lipocytes were positive for both antigens, suggesting the presence of transitional cells with mixed immunoreactivity. This was confirmed by ultrastructural studies which showed typical intraseptal myofibroblasts and other elements exhibiting the structural features of both myofibroblasts and lipocytes.

Actins↗
PubMed1987

Modification of macrophage differentiation: dimethylnitrosamine induced alteration in the responses towards the regulatory signals controlling myelopoiesis.

Results from our laboratory have demonstrated that the alteration in cellular immunity (CMI) resulting from exposure to dimethylnitrosamine (DMN) in vivo is due to changes in myelopoiesis. Bone marrow stem cells showed no alterations in their capacity to generate CFU-S (pleuripotent stem cells) nor were there any changes in the number of CFU-Mix colonies (IL-3 responsive stem cells) arising from the bone marrow of DMN exposed mice. However, the generation of G/M-CSF and CSF-1 responsive colonies (CFU-G/M and CFU-M) were altered, resulting in an increase in the number of colonies. G/M-CSF colonies generated from the bone marrow stem cells obtained from DMN exposed mice also had increased numbers of cells produced by each colony (total cells/CFU). Indirect immunofluorescence studies demonstrated no changes in the granulocyte/macrophage subsets following G/M-CSF stimulation of bone marrow stem cells obtained from DMN exposed mice. However, there was no change in the total number of cells generated by CSF-1 from the marrows of DMN exposed mice as compared to vehicle treated mice. Marrow cells from DMN exposed mice cultured in vitro with G/M-CSF showed both a shift in their peak proliferative response from 48-72 h to 30-60 h and an increased proliferative response. These same marrow cells showed no shift in their kinetics but a decrease in their proliferative response to CSF-1. Examination of the sera from DMN exposed mice for alterations in the regulatory factors controlling myelopoiesis demonstrated a net decrease of CSF-1 activity but no changes in the concentrations of two inhibitory factors, transferrin and lactoferrin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

DNA methylation in rat liver by daminozide, 1,1-dimethylhydrazine, and dimethylnitrosamine.

[methyl-14C]Daminozide (succinic acid 2',2'-dimethylhydrazide; 37 mg/kg), 1,1-[14C]dimethylhydrazine (UDMH; 19 mg/kg), and [14C]dimethylnitrosamine (DMNA; 0.1 mg/kg) were administered by oral gavage to male Sprague-Dawley rats. After 24 hr, the animals were killed and DNA was purified from the livers to constant specific radioactivity. After enzymatic degradation of the DNA to the 3'-deoxynucleotides the level of DNA methylation was determined by HPLC analysis. Radiolabeled 7-methylguanine (7mG) was identified by cochromatography with unlabeled 7mG added as standard after acidic depurination of DNA and HPLC analysis of purines and apurinic acid. All three compounds were found to methylate DNA. The relative potencies were 1:47:4900 for daminozide:UDMH:DMNA. With [methyl-3H]UDMH, the formation of 7mG was investigated as a function of dose administered, at 20, 2, and 0.2 mg/kg. The methylation of DNA was strictly proportional to the dose. The data were used to compare the level of DNA alkylation derived from residues of daminozide and UDMH in treated apple with the genotoxicity of the intake of N-nitroso compounds in Germany and Japan. It is estimated that these residues could lead to a DNA methylation in the liver of about 6% of an average exposure to DMNA.

Animals↗
PubMed1995

Percutaneous penetration of dimethylnitrosamine through human skin in vitro: application from cosmetic vehicles.

Human skin penetration of N-dimethylnitrosamine (DMN) from three vehicles has been determined in vitro. When applied as an infinite dose in isopropyl myristate (IPM, 1 microgram/microliter) the average total absorption over 48 hr was 2.6 +/- 1.2% of the applied dose (all data presented are expressed as means +/- standard errors). When applied as a finite dose in a representative oil-in-water emulsion vehicle the average total absorption over 48 hr was 4.0 +/- 0.3% of the applied dose. When applied as a finite dose in a representative shampoo vehicle for 10 min followed by rinsing (i.e. to represent in-use exposure conditions) the average total absorption over 48 hr was 1.1 +/- 0.1% of the applied dose. Approximately 72% of the DMN in the applied shampoo vehicle was removed by rinsing. There was considerable evaporative loss of DMN from the IPM and oil-in-water emulsion vehicles, such that absorption was complete within 3 hr of application. The overall data indicate that DMN can penetrate the skin rapidly but that in practice the amount actually available for penetration is significantly reduced by high permeant volatility. In contrast, application of N-nitrosodiethanolamine (NDELA) at a concentration of 1 microgram/microliter as an infinite dose generated an average total absorption over 48 hr of 23.6 +/- 6.4%, representing a total flux of 103.9 +/- 28.4 micrograms/cm2. In the case of NDELA, no evaporative loss was evident.

Carbon Isotopes↗
PubMed1976

Studies on the in vitro metabolism of dimethylnitrosamine by rat liver.

The biotransformation of dimethylnitrosamine (DMN) to formaldehyde, generally attributed to the mediation of a demethylase enzyme associated with the microsomal mixed function oxidase system, has been investigated in rat liver preparations. All of the enzyme activity was found in the postmitochondrial fraction and the microsomes contained approximately 50% of this activity. The restoration of total activity resulting from the addition of the cytosol to the microsomal fraction was found to be due to presence of diffusible, heat-labile constituents in the cytosol. Enzyme kinetic studies revealed that DMN was metabolized to formaldehyde by either a multistep or a multicomponent process. DMN demethylase was found to be relatively stable to storage in contrast to cytochrome P-450 and a number of mixed function oxidase enzyme activities. In spectral interaction studies DMN was found to form an atypical interaction spertrum with either control, phenobarbitone-pretreated or phospholipid-depted microsomal preparations. DMN had little effect on Type II spectral interaction of aniline, but noncompetitvely inhibited the Type I spectral interaction of benzphetamine and biphenyl. Whilst the mixed function oxidase enzyme inhibitors SKF 525A and metyrapone markedly reduced the metabolism of ethylmorphine and anailine, DMN demethylase was little affected by the former compound and appreciably enhanced by metyrapone. Moreover, DMN demethylase was strongly inhibited a number of hepatic mixed function oxidases, but significantly reduced anaerobic nitroreductase activity. The results of these studies reveal important differences between the properties of the enzymatic systems which metabolize DMN and mixed function oxidase substrates, and are consistent with the conclusion that the degradation of DMN to formaldehyde by rat liver preparations is a multicomponent system not rate limiting with respect to cytochrome P-450.

Animals↗
PubMed1983

DNA breaks induced by micromolar concentrations of dimethylnitrosamine in liver primary cell cultures from untreated and phenobarbital treated rats.

Direct genotoxic effects of the alkylating agent dimethylnitrosamine (DMN) have been difficult to detect in several short-term tests. We simplified our method to detect DNA breaks induced by DMN in rat liver primary cell cultures, and increased its sensitivity about 150 times by changing the conditions of ultracentrifugation and exposure to DMN. Additionally we increased 4 times the sensitivity of the improved assay by isolating hepatocytes from rats treated with phenobarbital (PB). Treatment for 24 h with 60 microM and 13.5 microM DMN of hepatocytes isolated from untreated and PB-treated rats, respectively, decreased the molecular weight of DNA by 50%. After 24 h exposure to 13.5 microM [14C]DMN, hepatocytes from PB-treated rats incorporated 3 times more radioactivity into trichloroacetic acid precipitable material than hepatocytes from untreated rats. Also PB-treatment increased remarkably cytotoxic effects of DMN while it did not modify the cytotoxicity nor the genotoxicity of the direct-acting alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine. These results show that DMN is more genotoxic for hepatocytes from PB-treated rats, and suggest that the enhanced genotoxicity is probably due to an augmented metabolism of DMN by these cultures. Our improved assay of DNA breaks as an indicator of DMN genotoxicity is now as sensitive but faster to perform than hepatocyte-mediated mutagenesis. It could be used to explore genotoxic effects of other alkylating agents and the action of microsomal enzyme modifiers on genotoxicity.

Animals↗
PubMed1990

Role of metabolism in dimethylnitrosamine-induced immunosuppression: a review.

Dimethylnitrosamine (DMN) has been characterized as a potent hepatotoxin, carcinogen and mutagen. As described below, immunotoxicity should be added to its profile of activity. Although a broad spectrum of immune parameters is affected by DMN, humoral immunity is particularly sensitive. In order for DMN to produce its traditional profile of toxicity it requires metabolic activation to reactive intermediates which alkylate macromolecules. Similarly, DMN also must be metabolized to produce its immunological effects. However, as this review suggests, the metabolism of DMN to an intermediate capable of suppressing the humoral immune response may be qualitatively and/or quantitatively different from that which mediates hepatotoxicity and genotoxicity.

Animals↗
PubMed1992

Importance of hepatocyte culture conditions in dimethylnitrosamine-induced suppression of antibody response in the mixed cultures of murine hepatocytes and splenocytes.

The role of the hepatocyte culture media in dimethylnitrosamine (DMN)-induced suppression of antibody responses by splenocytes against sheep erythrocytes (SRBCs) was investigated using the mixed culture system of murine hepatocytes and murine splenocytes. It was observed that hormone-supplemented complete media was required for hepatocyte cultures to optimally activate DMN to its immunosuppressive form(s). In the absence of the hormone supplement, the concentration of DMN required to produce a 50% suppression (IC50) was increased by over 10-fold (i.e., compare the IC50 in complete media of less than 0.5 mM to the IC50 in basal media of almost 10.0 mM). In contrast, the activation of cyclophosphamide (cytoxan, CTX), which was used in these studies as a comparative control, was not affected by the absence of the hormone supplement. These results indicate that the observed effect on the activation of DMN was not due to a generalized loss of metabolic capability of hepatocytes cultured without hormones. To examine the role of drug metabolizing capabilities of hepatocytes in the differential activation of DMN, we compared phase I and phase II enzyme activities of hepatocytes cultured for 24 h in either basal media or hormone-supplemented complete media. Our results indicated that there was a significant decrease of phase I monooxygenase activities of cultured hepatocytes when compared to freshly isolated hepatocytes. However, our results failed to show any difference in the activities of hepatocytes cultured in the two media. Most notably, there was no difference in the activity of either high- or low-affinity DMN demethylase, as measured by the generation of formaldehyde. We observed a similar profile with phase II conjugative capabilities, specifically sulfotransferase and glucuronyltransferase. These results indicate that the activation of DMN to its immunosuppressive form(s) can be modulated in the co-culture system by culturing hepatocytes under different conditions. Because we failed to show any differences in the metabolic capabilities of hepatocytes cultured under the two media conditions, the results suggest that the modulation of immunosuppressive activity may not be related to a change in the generation of the immunosuppressive metabolite(s).

Animals↗
PubMed1994

Role of hydrocortisone in dimethylnitrosamine-induced suppression of antibody response in the mixed culture of murine hepatocytes and splenocytes.

We have previously reported that the hormone-supplemented culture condition for primary hepatocytes is required in dimethylnitrosamine (DMN)-induced suppression of antibody response to sheep erythrocytes in the mixed cultures of murine hepatocytes and splenocytes. In the present investigation, the components of the hormone supplement were screened to identify the component(s) responsible for the increased ability of hepatocytes to activate DMN to its immunosuppressive form. The presence of hydrocortisone in the hepatocyte culture media had the primary role in DMN activation in the co-culture system. Other components of the hormone supplement showed slight or no effects. The effects of hydrocortisone were clearly confirmed through the dose-response study of both DMN and hydrocortisone. To characterize whether the effect of hydrocortisone is glucocorticoid-dependent we tested another potent glucocorticoid, dexamethasone (DEX), and determined if the activity by hydrocortisone could be reversed by RU 486. It was found that hepatocytes cultured in DEX-containing media could also activate DMN to its immunosuppressive form. However, the activity by hydrocortisone to increase DMN-induced immunosuppression was not reversed by RU 486. Furthermore, a possible direct interaction between DMN and hydrocortisone was ruled out. Finally, we transferred DMN-pre-treated culture supernatant from hepatocytes to spleen cell cultures, and found that the metabolite of DMN was very unstable, and that DMN-induced suppression of T-dependent antibody response was hepatocyte-dependent. The present results suggest that glucocorticoids, including hydrocortisone and DEX, in hepatocyte culture media can affect DMN-induced immunosuppression in the hepatocyte/splenocyte co-culture system via a pathway which does not appear to be related to the glucocorticoid receptor.

Animals↗
PubMed1980

Isolation of a morphologically-transformed epithelial cell-line from rat kidney following an in vivo dose of dimethylnitrosamine.

In an in vivo-in vitro system, a rat kidney epithelial cell-line was isolated into continuous culture 48 h after a single administration intraperitoneally of dimethylnitrosamine (DMN). The dose used, 60 mg/kg, was known to induce approximately a 40% incidence of renal cortical epithelial umors, in addition to a much higher incidence of renal mesenchymal tumors. The cell-line was established from several persisting islands of epithelial cells which were cultured in Leibowitz medium supplemented with various-growth enhancing agents and periodically, the antifibroblastic agent cishydroxyprolin. Through succeeding subcultures, the cells retained an epithelial morphology and at confluence piled-up into 3-dimensional ridges and domes above the monolayer. The cells were characterized by continuous growth in culture, the ability to form colonies at very low seeding rates, loss of anchorage-dependence as determined by growth in semi-solid media and formation of multicellular aggregates in suspension culture, and agglutination in the presence of conconavalin A. These altered properties of growth and behavior indicate that the renal epithelial cells constitute a morphologically transformed line. As such, they may represent the same target cell population from which DMN-induced epithelial tumors arise in the rat kidney.

Animals↗
PubMed1980

Comparative effects of indole and aminoacetonitrile derivatives on dimethylnitrosamine-demethylase and aryl hydrocarbon hydroxylase activities.

The effect of in vivo administration of indole and five 3-indolyl derivatives including L-tryptophan, as well as of aminoacetonitrile and 3 of its derivatives, were studied on the carcinogen-metabolizing hepatic mixed-function oxidases dimethylnitrosamine (DMN)-demethylase I and II and aryl hydrocarbon hydroxylase (AHH). Indole, 3-indolylmethanol, 3-indolyl-acetonitrile, 3-indolylacetone and L-tryptophan induce AHH activity from 3- to 6-fold of the control level, whereas beta-3-indolylethanol has no effect; the latter compound produces a 21% decrease of the endoplasmic reticulum content in the tissue. Only L-tryptophan induces DMN-demethylase I and only L-tryptophan and 3-indolylmethanol induce DMN-demethylase II, representing a doubling of enzyme activity in all 3 instances. Aminoacetonitrile is a potent repressor of DMN-demethylase I. Substitutions on the amino group bring about strong decrease or abolishment of mixed-function oxidase repressor activity; thus, iminodiacetonitrile has only about 1/5th the repressor activity of the parent compound, whereas nitrilotriacetonitrile and dimethylaminoacetonitrile appear to be inactive. Aminoacetonitrile and its derivatives studied have no effect on DMN-demethylase II and AHH activities. The mixed-function oxidase-modifying effects of the indole compounds and of aminoacetonitrile and its derivatives illustrate the potential complexity of effects of dietary constituents on the carcinogenic responses.

Acetonitriles↗
PubMed1983

No response of pigeon liver to dimethylnitrosamine acute effects.

No evidence for liver necrosis was observed at 24, 48 or 72 h after injection of dimethylnitrosamine (DMN) (70 mg/kg, i.p.) to pigeons. The assessment of possible liver necrosis was made by determination of isocitric dehydrogenase (ICD), glutamate oxalacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) in plasma. The ability of pigeon liver slices to metabolize CO2 or to give covalent binding of reactive metabolites to nucleic acids was 24 times smaller than that for rat. Similarly, the pigeon liver microsomes or 9000 X g supernatant have DMN-demethylase activity or ability to activate DMN to reactive metabolites that bind covalently to proteins very close to zero. Results suggest that resistance of pigeon liver to DMN acute effects is related to its lack of ability for DMN metabolic activation.

Alanine Transaminase↗
PubMed1983

Transient structural change in hepatic DNA of rats chronically exposed to dimethylnitrosamine.

Structural analysis by chromatography on benzoylated-DEAE-cellulose (BD-cellulose) has been made of hepatic DNA from rats treated for up to 21 weeks with dimethylnitrosamine (DMN). The carcinogen (1 mg/kg body wt) was administered on a daily basis by intraperitoneal injection. By comparison with preparations from saline-treated controls, the proportion of DNA retained by benzoylated-DEAE-cellulose in the presence of 1.0 M NaCl was increased by administration of the carcinogen. Variation in the result, dependent upon the time after the final dose, suggested a complex relationship between structural damage to DNA and duration of treatment. Structural damage was confirmed by S1 nuclease digestion. The observations imply that in the course of chronic administration, increasing time is required to complete DNA repair processes operative in rat liver.

Animals↗
PubMed1986

Differential effects on the metabolism of dimethylnitrosamine and aflatoxin B1 by hepatic microsomes from senescent rats.

The ability of hepatic microsomes from senescent rats to metabolize the two potent hepatocarcinogens dimethylnitrosamine (DMN) and aflatoxin B1 (AFB1) was investigated. Seven and 24-month-old male Sprague-Dawley rats were used. Liver weights, and microsomal protein per gram tissue weight were higher, whereas cytochrome P-450 and cytochrome b5 were significantly lower in older rats. Glutathione S-transferases and NADPH cytochrome c reductase activities were dramatically reduced in senescent rats. There was no difference in the formation of formaldehyde from DMN in vitro (31 vs. 34 pmol/nmol P-450) between the young and old rats. In contrast, increased microsome mediated binding of AFB1 to DNA was observed in older rats (116 vs. 228 pmol/nmol P-450) suggesting the possibility of either quantitative or qualitative changes in P-450 species. Additionally the cytoplasmic GSH S-transferases from older rats affected lower inhibition of binding of AFB1 to DNA. These results indicated differential abilities in the hepatic microsomal metabolism of these two carcinogens which may cause differential effects of these carcinogens in senescent rats.

Aflatoxin B1↗
PubMedDate not supplied

Effect of phenobarbital on diethylnitrosamine and dimethylnitrosamine induced hepatocellular tumors in male B6C3F1 mice.

The effect of the type of carcinogen initiator on the ability of phenobarbital (PB) to promote hepatic tumor formation in 15-day-old initiated male B6C3F1 mice was evaluated. Fifteen-day-old male B6C3F1 mice were divided into 6 groups of 10 mice each. Groups 1 and 2 received a single intraperitoneal (i.p.) injection of diethylnitrosamine (DENA) (5 micrograms/body wt). Groups 3 and 4 received a single i.p. injection of diethylnitrosamine (DENA) (5 micrograms/g body wt). Groups 3 and 4 received a single i.p. injection of dimethylnitrosamine (DMNA) (5 micrograms/g body wt). Groups 5 and 6 received a single i.p. injection of saline. At weaning (28 days of age), mice in groups 2, 4 and 6 received PB (500 mg/ml) in their drinking water. Mice in groups 1, 3 and 5 received deionized drinking water. Drinking water treatment continued for 24 weeks at which time mice were sampled. At sampling, mice were examined for hepatic tumors by histology. Mice in groups 5 (no treatment) and 6 (PB only) did not exhibit hepatic tumors. Groups 2 (DENA + PB) displayed a decrease in hepatic adenomas from that of group 1 (DENA only), confirming previous observations. Treatment with DMNA and PB (group 4), however, resulted in a significant increase in both hepatic adenoma incidence and number over that of DMNA only (group 3) treated mice. The promoted adenomas appeared to be predominantly eosinophilic in appearance. The type of initiator therefore appears important in determining if 15-day-old initiated male B6C3F1 mice respond to the promotion effects of PB.

Adenoma↗
PubMed1989

Immunocytochemical analysis of O6-alkylguanine shows tissue specific formation in and removal from esophageal and liver DNA in rats treated with methylbenzylnitrosamine, dimethylnitrosamine, diethylnitrosamine and ethylnitrosourea.

The formation and repair of carcinogen-DNA adducts in esophagus and liver of rats treated with a single i.p. dose of methylbenzylnitrosamine (MBN), dimethylnitrosamine (DMN), diethylnitrosamine (DEN) or ethylnitrosourea (ENU) has been studied using peroxidase immunocytochemistry to visualize O6-alkylguanine in DNA of individual cells. After MBN O6-methylguanine (O6-MeG) specific nuclear staining was only present in the target tissue for tumor induction, the esophageal epithelium. Part of the adducts persisted for at least 72 h. No O6-MeG could be detected in liver. DEN, a carcinogen in liver and esophagus, led to DNA modification of esophageal epithelial cells, and liver parenchymal and non-parenchymal (Kupffer and sinusoidal) cells of the centrilobular area. O6-EtG was removed within 72 h from both liver cell populations. A similar distribution of adduct (O6-MeG) formation was observed in liver after the hepatocarcinogen DMN, but this nitrosamine did not detectably modify esophageal cells. O6-MeG persisted in Kupffer and especially sinusoidal lining cells of liver, consistent with the induction of sarcomas by DMN. The relatively unspecific, directly alkylating carcinogen ENU modified DNA of all cell types to a similar extent. A qualitative correlation was obtained between the tissue specific ability to induce tumors and the formation of O6-alkylguanine (O6-alkylG). Our experiments support the hypothesis that DNA modification is necessary for the initiation of carcinogenesis by chemical carcinogens, and that a low capacity to repair promutagenic lesions, like O6-alkylG, potentiates this process.

Animals↗
PubMed1990

Enhancement of dimethylnitrosamine-induced glutathione S-transferase P-positive hepatic foci by Clonorchis sinensis infestation in F344 rats.

The modifying potential of Clonorchis sinensis (CS) infestation on dimethylnitrosamine (DMN)-induced hepatocarcinogenesis was studied in male F344 rats. The metacercariae of CS were infected, 60 to each animal, by a single intragastric intubation at various times, before, during or after an 8-week period of DMN (25 ppm in drinking water) treatment. Controls were treated with DMN alone or infected with CS without carcinogen. Animals killed at the end of the 40-week experimental period showed a significant enhancing effect of CS on GST-P+ foci induction when CS was infected 4 weeks before DMN treatment, although no such influence was evident with CS infection during or following DMN exposure. The present findings suggest that CS might facilitate the proliferation of DMN-induced preneoplastic lesions of liver in rats.

Animals↗
PubMed1994

Strong promoting effect of Opisthorchis viverrini infection on dimethylnitrosamine-initiated hamster liver.

Continuous administration of dimethylnitrosamine (DMN) to Syrian hamsters infected with the liver fluke, Opisthorchis viverrini (OV) results in a 100% incidence of cholangiocellular carcinomas. In a two-stage experiment, however, dosing with liver flukes caused only a few lesions to develop (Flavel, D.J. and Lucus, S.B. (1983) Carcinogenesis, 4, 927]. To clarify this anomaly, Syrian hamsters were initiated with 20 mg/kg DMN injected i.p. 19 days prior to 80 OV metacercaria infection. At 45 weeks, the animals receiving both DMN and the parasite demonstrated a 44% incidence of cholangiocarcinomas, a 93% incidence of cholangiofibrosis, a 35% incidence of mucous cystadenomas and a 98% incidence of hepatocellular nodules with an average number of 9.1 +/- 4.1 per animal. Animals receiving DMN alone developed 85% hepatocellular nodules with an average number of only 3.0 +/- 2.7 and no bile duct lesions. In the parasite alone group, only cholangiofibrosis was detected in a few animals and no lesions were encountered in untreated controls. These results thus demonstrate that the post-initiation influence of Opisthorchiasis is indeed effective in promoting the development of both cholangiolar and hepatocellular lesions initiated by DMN.

Animals↗